A growing trend in the pharmaceutical industry is to market chiral drugs in enantiomerically pure form to provide desired positive effects in humans. Production of enantiomerically pure compounds is important for several reasons. First, one enantiomer often provides a desired biological function through interactions with natural binding sites, but another enantiomer typically does not have the same function or effect. Further, it is possible that one enantiomer has harmful side effects, while another enantiomer provides a desired positive biological activity. To meet this demand for chiral drugs, many approaches for obtaining enantiomerically pure compounds have been explored such as diastereomeric resolution, structural modification of naturally occurring chiral compounds, asymmetric catalysis using synthetic chiral catalysts and enzymes, and the separation of enantiomers using simulated moving bed (SMB) technology.
Asymmetric catalysis is often the most efficient method for the synthesis of enantiomerically enriched compounds because a small amount of a chiral catalyst can be used to produce a large quantity of a chiral target molecule. Over the last two decades, more than a half-dozen commercial industrial processes have been developed that use asymmetric catalysis as the key step in the production of enantiomerically pure compounds with a tremendous effort focused on developing new asymmetric catalysts for these reactions (Morrison J. D., ed. Asymmetric Synthesis, New York: Academic Press, 1985:5; Bosnich B., ed. Asymmetric Catalysis, Dordrecht, Netherlands: Martinus Nijhoff Publishers, 1986; Brunner H. Synthesis, 1988:645; Noyori R., Kitamura M., in Scheffold R., ed. Modern Synthetic Methods, Berlin Hedelberg: Springer-Verlag, 1989;5:115; Nugent W. A., RajanBabu T. V., Burk M. J. Science, 1993;259:479; Ojima I., ed. Catalytic Asymmetric Synthesis, New York: VCH, 1993; Noyori R. Asymmetric Catalysis In Organic Synthesis, New York: John Wiley & Sons, Inc, 1994).
Chiral phosphine ligands have played a significant role in the development of novel transition metal catalyzed asymmetric reactions to produce enantiomeric excess of compounds with desired activities. The first successful attempts at asymmetric hydrogenation of enamide substrates were accomplished in the late 1970s using chiral bisphosphines as transition metal ligands (Vineyard B. D., Knowles W. S., Sabacky M. J., Bachman G. L., Weinkauff D. J. J. Am. Chem. Soc. 1977;99(18):5946-52; Knowles W. S., Sabacky M. J., Vineyard B. D., Weinkauff D. J. J. Am. Chem. Soc. 1975;97(9):2567-8).
Since these first published reports, there has been an explosion of research geared toward the synthesis of new chiral bisphosphine ligands for asymmetric hydrogenations and other chiral catalytic transformations (Ojima I., ed. Catalytic Asymmetric Synthesis, New York: VCH Publishers, Inc, 1993; Ager D. J., ed. Handbook of Chiral Chemicals, Marcel Dekker, Inc, 1999). Highly selective rigid chiral phospholane ligands have been used to facilitate these asymmetric reactions. For example, phospholane ligands are used in the asymmetric hydrogenation of enamide substrates and other chiral catalytic transformations.
BPE, Duphos, and BisP ligands are some of the most efficient and broadly useful ligands developed for asymmetric hydrogenation to date (Burk M. J. Chemtracts 1998;11(11):787-802 (CODEN: CHEMFW ISSN:1431-9268. CAN 130:38423; AN 1998:698087 CAPLUS); Burk M. J., Bienewald F., Harris M., Zanotti-Gerosa A. Angew Chem., Int. Ed. 1998;37(13/14):1931-1933; Burk, M. J., Casy G., Johnson N. B. J. Org. Chem. 1998;63(18):6084-6085; Burk M. J., Kalberg C. S., Pizzano A. J. Am. Chem. Soc. 1998;120(18):4345-4353; Burk M. J., Harper T., Gregory P., Kalberg C. S. J. Am. Chem. Soc. 1995;117(15):4423-4424; Burk M. J., Feaster J. E., Nugent W. A., Harlow R. L. J. Am. Chem. Soc. 1993;115(22):10125-10138; Nugent W. A., RajanBabu T. V., Burk M. J. Science (Washington, D.C. 1883-) 1993;259(5094):479483; Burk M. J., Feaster J. E., Harlow R. L. Tetrahedron: Asymmetry 1991;2(7):569-592; Burk M J. J. Am. Chem. Soc. 1991;113(22):8518-8519; Imamoto T., Watanabe J., Wada Y., Masuda H., Yamada H., Tsuruta H. et al. J. Am. Chem. Soc. 1998;120(7):1635-1636; Zhu G, Cao P, Jiang Q, Zhang X. J. Am. Chem. Soc. 1997;119(7):1799-1800). For example, a Rhodium/Duphos complex can be used to selectively form (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid, known as pregabalin, which is used as an anti-seizure drug. The S-enantiomer, which is produced in enantiomeric excess, is preferred because it shows better anticonvulsant activity than the R-enantiomer (Yuen et al., Bioorganic & Medicinal Chemistry Letters 1994;4:823).
The success of BPE, DuPhos, and BisP transition metal complexes in asymmetric hydrogenations is derived from many factors. For example, substrate to catalyst ratios of up to 50,000/1 have been demonstrated. Also, high rates of substrate conversion to product using low hydrogen pressures have been observed with catalysts made from these ligands.
BPE, Duphos, and BisP have shown high enantioselectivities in numerous asymmetric reactions. Improved reaction of BPE, Duphos, and BisP is attributed to, among other factors, rigidity in their C2-symmetric structure. If the spatial area of a metal/phosphine ligand structure, such as BisP, is divided into four quadrants, as shown in Scheme 1, alternating hindered and unhindered quadrants are formed.
This structural feature creates areas of hindrance in the BisP/metal complexes and produces desired stereochemical results in asymmetric hydrogenation reactions. However, there are a variety of reactions in which only modest enantioselectivity has been achieved with these ligands. While high selectivity has been observed in many reactions using these chiral diphosphine ligands, there are many reactions where these ligands are not very efficient in terms of activity and selectivity. Further, there are many disadvantages associated with these ligands, which limits their application.
For example, multiple chiral centers in these ligands increases the difficulty in synthesis of these compounds. Further, the multiple chiral centers could increase the cost associated with forming the ligands.
High enantioselectivities have been observed in asymmetric hydrogenation for a narrow range of substrates, such as enamides, enol esters, and succinates. Many of these successful results have been obtained using optically pure C2-symmetric rhodium-phosphine complexes as hydrogenation catalysts. Therefore, C2-symmetry has become a popular characteristic in the design of chiral ligands that are used to make these complexes. Unique to the substrates for which asymmetric hydrogenation has been successful is an olefin and a carbonyl group which are separated by one atom. During asymmetric hydrogenation, the olefin and the carbonyl bind to the metal center in a well-defined conformation. This is thought to be of consequence in an asymmetric hydrogenation.
C2-symmetric bisphosphines, such as BisP, have been synthesized and used in asymmetric catalysis, as shown in Scheme 2 (Imamoto, T., Watanabe J., Wada Y., Masuda H., Yamada H., Tsuruta H., Matsukawa S., Yamaguchi K. J. Am. Chem. Soc. 1998;120(7):1635-1636).
A proton from one of the methyl groups of tert-butyldimethyl phosphine is selectively deprotonated with a chiral base, such as s-BuLi and (−)-sparteine, and then the resulting anion couples with itself in the presence of copper(II) chloride to provide the bisphosphine borane protected ligand, in about 40% yield and >99% enantiomeric excess after recrystallization. The rhodium complex of BisP is known to give high enantiomeric excess in hydrogenation reactions for a variety of substrates. For instance, the rhodium-BisP catalyst hydrogenates α-N-acetylmethylacrylate to produce 98% enantiomeric excess (Imamoto T. et al., supra, 1998).
A drawback to the synthesis of the BisP ligand in Scheme 2 is that only one antipode of sparteine is available in nature, and therefore, only one enantiomer of the ligand (the S,S isomer) can be synthesized via this route.
Basic research has been done by a variety of groups in the late 1970s on the mechanism and origin of enantioselectivity of asymmetric hydrogenation reactions which result in high enantiomeric excess (Alcock N. W., Brown J. M.; Derome A. E., Lucy A. R. J. Chem. Soc. Chem. Comm. 1985:575; Brown J. M., Chaloner P. A., Morris G. A. J. Chem. Soc. Chem. Comm. 1983:664; Halpern J. Science 1982;217,401; Brown J. M., Chaloner P. A. J. Chem. Soc. Chem. Comm. 1980;344). The 3-dimensional structure of a C2-symmetric complex like the rhodium complex of BisP has four quadrants that alternate hindered and unhindered, as shown in Scheme 1.
Ligand and metal/ligand complexes are needed that can further improve the production of enantiomerically active forms of compounds. Thus, there is a need to develop methods for the production of and to synthesize compounds that reduce the number of chiral centers on a molecule and through prohibitive substituents on the ligand improve enantioselectivity in asymmetric reactions.